We hypothesize that altered responsiveness of central stress circuits within the emotional motor system (EMS) can explain many of the cardinal symptoms of Irritable Bowel Syndrome (IBS) as well as other functional visceral disorders such as Interstitial Cystitis (IC). Growing evidence indicates that key components of central stress circuits are sexually dimorphic and differentially responsive in men and women. In particular we hypothesize that female-specific modulators (estrogen, oxytocin systems) of these stress circuits play an important role in the modulation of afferent input from, and efferent output to, the pelvic viscera in patients with IBS and IC. Alterations of brain circuits involving pontine nuclei (locus coeruleus, Barrington's nucleus, parabrachial nucleus, and periaqueductal grey), cortical regions (ventromedial prefrontal cortex, anterior cingulate and insular cortex), and the amygdala complex, may be central to these sex-related differences in pain and stress symptoms. We propose to test specific hypotheses regarding sex-related differences in central stress responses in healthy controls and patients with IBS and IC, using visceral and psychological stress paradigms related to visceral discomfort. Central responses will be examined using (in separate studies) acoustic startle modulation and fMRI. Amygdala complex responsivity will be tested using startle enhancement associated with both viscero-pelvic and non-visceral fear. Differential activation of targeted brain regions to visceral stimulation and anticipation of stimulation will be tested using fMRl. Peripheral and central (from cerebro spinal fluid) concentrations of stress-related neuromodulators including corticotropin relasing factor, norepinephrine and oxytocin will be assessed for gender and illness group interactions and as correlates of the functional measures. These studies will address three specific aims: 1) Are there sex-related differences in central stress and attention responses in healthy controls and/or IBS/IC patients? 2) Are there sex-related alterations in EMS activation in response to psychological or visceral stressors? and 3) Are there alterations in central stress neurotransmitters/modulators consistent with enhanced EMS network activation in women with IBS/IC?